Endometrial cancer is the most common malignancy in the female reproductive tract and accounts for 6% of all cancer in women. Obesity is a well-known risk factor for endometrial cancer such that up to 40% of endometrial cancer is attributed to excess adiposity, and morbidly obese women have a 6-fold increased risk of dying from this disease. The link between obesity and endometrial cancer is poorly understood, but risk factors include insulin resistance, glucose intolerance, low-grade inflammation, and elevated sex hormones. In addition, recent epidemiologic studies identified a link between increased dietary intake of sugar and endometrial cancer. Most of the studies linking obesity and sugar to endometrial cancer are correlative. A major barrier to defining the precise mechanisms whereby obesity and sugar drive endometrial cancer is the lack of an experimental animal model where endometrial cancer can be induced by feeding an obesigenic diet. The overarching goal of this pilot project is to generate and characterize the first diet-induced mouse models of endometrial cancer. We observe that deletion of one allele of the tumor suppressor LKB1 in the mouse endometrium confers diet-sensitive susceptibility to endometrial cancer. Herein, we will investigate the contribution of 2 different tumor suppressors associated with endometrial cancer development in humans, LKB1 and PTEN, by deleting each individually in the mouse epithelial endometrium using Cre-lox mediated deletion. We will test 2 different systems to delete floxed LKB1 or PTEN exons in the endometrial epithelium using transgenic mice that express Cre under the control of either the Sprr2f or Pax8 promoters. We hypothesize that consumption of a high fat/high sugar (Western) diet will accelerate endometrial tumor formation and progression in mice lacking one or both copies of the tumor suppressors LKB1 or PTEN in the endometrial epithelium. This hypothesis will be tested in two Specific Aims. Aim 1 will fully characterize the incidence and kinetics of endometrial cancer and potential metastatic progression in mice with heterozygous deletion of LKB1 achieved by Sprr2f-dependent expression of Cre. Aim 2 will employ a tetracycline-inducible Pax8- Cre system to delete LKB1 or PTEN in adult mice and evaluate the incidence and kinetics of tumor development in mice fed diets containing high fat or low fat. At a minimum, we expect to produce at least one model of endometrial cancer that is responsive to diet. This model would fill a significant void in the field and enable additional investigation of the role of specific dietary factors as well as molecular mechanisms in the regulation of endometrial cancer. The ability to manipulate the timing of LKB1 or PTEN loss (with inducible Pax8-Cre expression) in the context of Western diet feeding would facilitate future studies examining the effects of age, parity, and hormonal status in obesity-related endometrial cancer.